This project aims to delineate functional immune responses to the human immunodeficiency viruses (HIVs), and to identify viral subfragments which elicit protective humoral and cellular immunity to HIV-1 and -2 and simian immunodeficiency virus (SIV). Studies of neutralizing antibody to the MN isolate revealed that titers >225 were correlated with less severe disease in HIV-infected children. This titer was also predictive of clinical outcome in patients with >10% of normal median age-adjusted CD4 cell count. Patients with titers <225 more often encountered major clinical events in follow-up than patients with titers >225. Thus, preservation of neutralizing antibody should be considered in passive and active immune therapy strategies. Extensive cross-neutralizations seen between HIV-2 and SIV reflect common neutralizing epitopes. The V3 loop sequences of these viruses do not appear to constitute linear neutralizing epitopes. Alternate subunits expressing conformational epitopes may be needed to exploit HIV-2 and SIV as vaccine models. Studies of viral variation and immune escape have emphasized that alternate conformationally determined epitopes are as important as the V3 loop in HIV-1 neutralization, and immune pressure is not the sole influence on variant selection. A reverted HIV escape mutant was selected during long-term culture due to a lesser cytopathic effect. Cellular immune responses to HIV-1 and -2 and SIV reflect homology with previously identified HIV-1 epitopes. Identification of a cross-reactive cytotoxic T lymphocyte epitope in HIV-1 and -2 envelopes after immunization of mice with vaccinia-env recombinants may assist design of broadly reactive vaccines. Functional immune responses elicited by live vectors, such as attenuated vaccinia, avipox, and adenovirus, carrying HIV genes are being assessed. Adenovirus-HIV-envelope recombinants have shown great promise. Dogs immunized sequentially with distinct serotypes of adeno-HIV recombinants developed high-titer HIV neutralizing antibodies, and adenovirus expressed HIV envelope effectively boosted the immune response. Future trials of adeno-HIV vaccines in chimpanzees will assess a live virus challenge.